Hypoxia Attenuates Pressure Overload-Induced Heart Failure

verfasst von: Natali Froese, Malgorzata Szaroszyk, Paolo Galuppo, Joseph R. Visker, Christopher Werlein, Mortimer Korf-Klingebiel, Dominik Berliner, Marc R. Reboll, Rana Hamouche, Simona Gegel, Yong Wang, Winfried Hofmann, Ming Tang, Robert Geffers, Adam R. Wende, Mark P. Kühnel, Danny D. Jonigk, Georg Hansmann, Kai C. Wollert, E. Dale Abel, Stavros G. Drakos, Johann Bauersachs, Christian Riehle
Abstract: Background Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support. Methods and Results We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Conclusions Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.
Organisationseinheit(en): Forschungszentrum L3S
Externe Organisation(en): Medizinische Hochschule Hannover (MHH)
University of Utah
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
University of Alabama at Birmingham
Deutsches Zentrum für Lungenforschung (DZL)
Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU Erlangen-Nürnberg)
University of California (UCLA)
Typ: Artikel
Journal: Journal of the American Heart Association
Band: 13
Anzahl der Seiten: 16
ISSN: 2047-9980
Publikationsdatum: 06.02.2024
Publikationsstatus: Veröffentlicht
Peer-reviewed: Ja
ASJC Scopus Sachgebiete: Kardiologie und kardiovaskuläre Medizin
Elektronische Version(en): https://doi.org/10.1161/JAHA.123.033553 (Zugang: Offen)

BibTeX

@article{2a00f4035d364732b8e5136c4765fcd1,
title = "Hypoxia Attenuates Pressure Overload-Induced Heart Failure",
abstract = "Background Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support. Methods and Results We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Conclusions Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.",
keywords = "cardiac hypertrophy, cardiac remodeling, hypoxia, left ventricular assist device, pressure overload",
author = "Natali Froese and Malgorzata Szaroszyk and Paolo Galuppo and Visker, {Joseph R.} and Christopher Werlein and Mortimer Korf-Klingebiel and Dominik Berliner and Reboll, {Marc R.} and Rana Hamouche and Simona Gegel and Yong Wang and Winfried Hofmann and Ming Tang and Robert Geffers and Wende, {Adam R.} and K{\"u}hnel, {Mark P.} and Jonigk, {Danny D.} and Georg Hansmann and Wollert, {Kai C.} and Abel, {E. Dale} and Drakos, {Stavros G.} and Johann Bauersachs and Christian Riehle",
note = "Funding Information: This work was supported by a research grant of the German Heart Foundation to C.R. (F/32/18); the German Research Foundation (DFG) and the Clinical Research Unit (KFO) 311 to D.D.J., G.H., K.C.W., and J.B.; American Heart Association Heart Failure Strategically Focused Research Network 16SFRN29020000 to S.G.D.; National Heart, Lung, and Blood Institute R01 HL135121-01 and R01 HL132067-01A1 to S.G.D.; and Nora Eccles Treadwell Foundation Grant to S.G.D. ",
year = "2024",
month = feb,
day = "6",
doi = "10.1161/JAHA.123.033553",
language = "English",
volume = "13",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "3",
}